Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms

Gerd Wallukat; Bettina Hohberger; Katrin Wenzel; Julia Fürst; Sarah Schulze-Rothe; Anne Wallukat; Anne-Sophie Hönicke; Johannes Müller

doi:10.1016/j.jtauto.2021.100100

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms

J Transl Autoimmun. 2021:4:100100. doi: 10.1016/j.jtauto.2021.100100. Epub 2021 Apr 16.

Authors

Gerd Wallukat^{1

2}, Bettina Hohberger³, Katrin Wenzel², Julia Fürst⁴, Sarah Schulze-Rothe², Anne Wallukat², Anne-Sophie Hönicke², Johannes Müller²

Affiliations

¹ Experimental and Clinical Research Center, Charité Campus Buch, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
² Berlin Cures GmbH, Berlin; Germany.
³ Department of Ophthalmology, University of Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
⁴ Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.

Abstract

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (_fAABs) targeting G-protein coupled receptors (GPCR-_fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-_fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-_fAABs that acted as receptor agonists. Some of those GPCR-_fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-_fAAB detection). Other GPCR-_fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-_fAABs identified in the blood of Long-COVID patients targeted the β₂-adrenoceptor (β₂-_fAAB), the α₁-adrenoceptor (α₁-_fAAB), the angiotensin II AT1-receptor (AT1-_fAAB), and the nociceptin-like opioid receptor (NOC-_fAAB). The negative chronotropic GPCR-_fAABs identified targeted the muscarinic M₂-receptor (M₂-_fAAB), the MAS-receptor (MAS-_fAAB), and the ETA-receptor (ETA-_fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.

Keywords: ACE2, Angiotensin-converting enzyme 2 receptors; AT1-fAAB, Autoantibody targeting the angiotensin II AT1 receptor; Autoantibody; Autoimmunity; COVID-19; CRPS, Complex regional pain syndrome; ETA-fAAB, Autoantibody targeting the endothelin receptor; Fatigue; GPCR, G-protein coupled receptors; Long-COVID; M2-fAAB, Autoantibody targeting the muscarinic receptor; MAS-fAAB, Autoantibody targeting the MAS receptor; NOC-fAAB, Functionally active autoantibody against the nociceptin receptor; PoTS, Postural orthostatic tachycardia syndrome; Post-covid-19 symptom; RAS, Renin angiotensin system; SARS, Severe acute respiratory syndrome; fAAB, Functional autoantibody; α1-fAAB, Autoantibody targeting the alpha1-adrenoceptor; β2-fAAB, Autoantibody targeting the beta2-adrenoceptor.